CD147 and Corneal Wound Repair

描述(申请人提供)：角膜损伤后的愈合过程是通过释放一些蛋白质来启动的，这些蛋白质分解上皮连接，促进上皮层的移动，覆盖受伤的区域。基质金属蛋白酶(MMPs)是一类降解细胞表面和细胞外基质成分的蛋白水解酶，在这一过程中起着中心作用。在未受伤的角膜中几乎没有检测到它们的诱导，它们被认为在伤口愈合和慢性伤口的建立中发挥关键作用。MMPs的产生和激活受到复杂机制的严格调控，其中包括CD147的同源寡聚，CD147是一种高度N-糖基化的跨膜蛋白，在肿瘤细胞中高度表达。我们最近发现，CD147是Galectin-3的一种新的细胞表面反向受体，Galectin-3是一种已知与�乳糖苷结合的凝集素 细胞表面受体。更重要的是，我们发现Galectin-3对CD147的聚集显著上调了MMP9，MMP9是角膜上皮细胞迁移到伤口表面时合成和分泌的主要金属蛋白酶。这项建议的长期目标是确定Galectin-3诱导CD147聚集是否是与角膜创伤修复相关的生理和病理重塑过程的强大调节机制。具体目标如下：(1)研究Galectin-3诱导的CD147聚集作为角膜上皮细胞集体细胞脱离和细胞迁移的调节器的作用，并确定MMP9降解Galectin-3是否抑制CD147聚集，从而构成防止持续角膜重塑的负反馈机制，(2)研究CD147 N-糖基化在调节Galectin-3结合亲和力、CD147聚集和MMP9诱导中的作用，以及(3)表征CD147/Galectin-3复合体在小鼠创伤愈合和反复侵蚀模型中的生物学作用。并确定抑制Galectin-3受体聚集和CD147功能在复发性上皮创面愈合过程中是否具有治疗潜力。这项研究将首次探索将多糖动力学与创伤组织启动上皮细胞分离和迁移的生物过程联系起来的分子机制，并将为更好地了解慢性伤口的发病机制提供依据。

DESCRIPTION (provided by applicant): The healing process after corneal injury is initiated through the release of a number of proteins that disassemble the epithelial junctions and contribute to the movement of the epithelial sheet to cover the wounded area. Matrix metalloproteinases (MMPs), a family of proteolytic enzymes that degrade components of the cell surface and extracellular matrix, are central to this process. Barely detected in unwounded cornea, their induction is thought to play a key role during wound healing and in the establishment of chronic wounds. The production and activation of MMPs are tightly regulated by complex mechanisms that include homo-oligomerization of CD147, a heavily N-glycosylated transmembrane protein highly expressed in tumor cells. We recently discovered that CD147 is a novel cell surface counter-receptor for galectin-3, a �alactoside-binding lectin known to cluster cell surface receptors. More importantly, we found that clustering of CD147 by galectin-3 dramatically upregulates MMP9, the primary metalloproteinase synthesized and secreted by corneal epithelial cells migrating to resurface a wound. The long-term objective of this proposal is to determine whether induction of CD147 clustering by galectin-3 is a powerful regulatory mechanism of the physiological and pathological remodeling processes associated with wound repair in the cornea. The following specific aims will address this objective: (1) to investigate te role of CD147 clustering by galectin-3 as modulator of collective cell detachment and cell migration in corneal epithelial cells, and to determine whether degradation of the galectin-3 by MMP9 inhibits CD147 clustering, thereby constituting a negative feedback mechanism to prevent sustained corneal remodeling, (2) to investigate the role of CD147 N-glycosylation in modulating galectin-3 binding affinity, CD147 clustering, and MMP9 induction, and (3) to characterize the biological role of the CD147/galectin-3 complex in mouse models of wound healing and recurrent erosion, and determine whether inhibiting galectin-3 receptor clustering and CD147 function have a therapeutic potential during recurrent epithelial wound healing. This research will explore, for the first time, the molecular mechanism linking glycan dynamics to the biological process by which wounded tissue initiates epithelial cell detachment and migration, and will provide better insight into the pathogenesis of chronic wounds.